Bipolar disorder is a major psychiatric disorder that affects 1-2 percent of the world's population and consumes a substantial portion of mental healthcare dollars. Numerous twin and family studies have demonstrated a substantial heritable component, and family-based linkage studies have identified several susceptibility loci. Recently, the identification of large numbers of single nucleotide polymorphisms (SNPs) in the genome as part of the HapMap project and advances in high throughput array-based genotyping have made possible whole genome high density association analyses. Such an approach has the advantages of much greater power to detect genes of smaller effect, and gene-level resolution. Our consortium has been funded by NIMH for genetic studies of bipolar disorder since 1989. Together we have collected over 600 families with bipolar disorder and conducted one of the largest linkage studies to date that identified several possible susceptibility loci. We are presently funded by NIMH to collect a sample of 5,500 bipolar I subjects for large case-control studies. We also have access to a sample of 4,000 systematically ascertained control subjects collected as part of a separate study of schizophrenia. We propose to examine 500,000 SNP markers distributed at an average 6 kb density across the genome using an oligonucleotide microarray-based method, the Affymetrix 500K chip. Familial, early onset bipolar I cases will be selected for all phases of the study in order to maximize the genetic loading. In the first phase, 1,000 bipolar I Caucasian cases and 1,000 ethnically matched controls will be genotyped. These data will be analyzed using a variety of haplotype- based methods and employing several alternative clinically defined subphenotypes. Positive genes and regions will be selected based on statistical significance and clustering of associated SNPs, and genotyped in a phase 2 replication sample. This phase 2 sample will include a separate matched set of 2,000 Caucasian familial, early onset, bipolar I subjects and 1,000 Caucasian ethnically matched controls;a set of 400 Caucasian parents of a subset of the cases for TDT analysis;and an African-American sample of 400 bipolar I cases and 400 controls. Positive regions will be genotyped at high density using 10,000 SNPs using Affymetrix Molecular Inversion Probe technology and supplemented by three additional genotyping methods. This second phase of genotyping in an independent large sample will provide critical replication and the opportunity to examine gene-gene interactions and association in clinical subphenotypes. Identified genes will be examined using novel bioinformatics methods to identify possible disease pathways.